Steven Howard, MD, PhD headshot

Steven Howard, MD, PhD

Associate Professor (CHS)

Department of Human Oncology


Resident, Harvard University Medical School, Radiation Therapy (1995)

PhD, University of Wisconsin–Madison, Radiobiology (1991)

MD, University of Wisconsin–Madison, Medicine (1990)

BS, Illinois Benedictine College, Biochemistry/Chemistry (1980)

Academic Appointments

Associate Professor, Human Oncology (2006)

Assistant Professor, Human Oncology (1998)

Selected Honors and Awards

Best Doctors® in America (2013–2015)

Top Docs, Madison Magazine (2004, 2006, 2012)

Hodson Trust Scholar, Johns Hopkins School of Medicine (1995–1998)

Medical Scientist Training Program Trainee (1988–1990)

Magna Cum Laude with Distinction Chemistry and Biochemistry, Illinois Benedictine College (1980)

Boards, Advisory Committees and Professional Organizations

CHS Promotions Committee (Chair 2013), University of Wisconsin

Medical School Admissions Committee, University of Wisconsin (2007–pres.)

Study Section, Effects of Space Radiations on the Central Nervous System, NASA

Prostate Cancer Research Program Peer Reviewer (Radiation Oncology/Radiation Biology) U.S. Army Medical Research and Materiel Command (2003–2010)

Council of Faculty, University of Wisconsin (2002–pres.)

Medical Records Committee, University of Wisconsin (2002–pres.)

Credentials Committee, University of Wisconsin (2002–pres.)

Human Subjects Committee, University of Wisconsin (1998–1999)

Johns Hopkins Oncology Center Educational Committee (1995–1998)

Dr. Steven Howard has expertise in the treatment of patients with brain tumors. His research focuses on the clinical application of new radiation techniques and radiation-drug combinations to improve outcomes for brain tumor patients.

  • Mammary Paget's Disease as a Sign of Local Recurrence Two Decades Following Breast Conservation and Adjuvant Therapy for Early Stage Breast Cancer Cureus
    Afzal RJ, Basree MM, Howard SP, Xu J, Wilke LG, Anderson BM
    2024 Jun 2;16(6):e61521. doi: 10.7759/cureus.61521. eCollection 2024 Jun.
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      Reports of mammary Paget's disease (MPD) as a manifestation of breast cancer recurrence are rare. MPD presents a particular challenge when emerging more than two decades after a breast cancer treated with evidence-based therapy. There is a broad spectrum of non-malignant causes for dermatitis of the nipple during the initial presentation that may delay cancer work-up. This case highlights the MPD work-up and management in the context of a personal history of breast cancer. This unique clinical presentation emphasizes the importance of vigilant cancer surveillance for timely intervention, especially for a presumed cured cancer.

      PMID:38957233 | PMC:PMC11218596 | DOI:10.7759/cureus.61521

      View details for PubMedID 38957233
  • Pulsed reduced-dose rate re-irradiation for patients with recurrent grade 2 gliomas Neuro-oncology advances
    Harari CM, Burr AR, Morris BA, Tomé WA, Bayliss A, Bhatia A, Grogan PT, Robins HI, Howard SP
    2024 May 10;6(1):vdae073. doi: 10.1093/noajnl/vdae073. eCollection 2024 Jan-Dec.
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      BACKGROUND: Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced-dose rate (PRDR) radiation for patients with recurrent grade 2 glioma.

      METHODS: A retrospective analysis of 58 patients treated with PRDR from 2000 to 2021 was performed. Radiation was delivered in 0.2 Gy pulses every 3 minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan-Meier and Cox regression analyses.

      RESULTS: The median survival from the date of initial surgery was 8.6 years (95% CI: 5.5-11.8 years). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI: 8.3-17.0 months) and progression-free survival was 6.2 months (95% CI: 3.8-8.6 months). Overall response rate based on post-PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with 5 patients remaining disease-free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated.

      CONCLUSIONS: To the best of our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q codeletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.

      PMID:38845694 | PMC:PMC11154132 | DOI:10.1093/noajnl/vdae073

      View details for PubMedID 38845694
  • Case report: Radiographic complete response of radiation-induced glioblastoma to front-line radiotherapy: A report and molecular characterization of two unique cases Frontiers in neurology
    Grogan PT, Helgager JJ, Deming DA, Howard SP, Jenkins RB, Robins HI
    2023 Mar 21;14:1099424. doi: 10.3389/fneur.2023.1099424. eCollection 2023.
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      Radiation-induced gliomas (RIGs) are an uncommon disease type and a known long-term complication of prior central nervous system radiation exposure, often during childhood. Given the rarity of this malignancy subtype, no clinical trials have explored optimal therapy for these patients, and the literature is primarily limited to reports of patient cases and series. Indeed, the genomic profiles of RIGs have only recently been explored in limited numbers, categorizing these gliomas into a unique subset. Here, we describe two cases of RIG diagnosed as glioblastoma (GB), IDH-wildtype, in adults who had previously received central nervous system radiation for childhood cancers. Both patients demonstrated a surprising complete radiographic response of the postoperative residual disease to front-line therapy, a phenomenon rarely observed in the management of any GB and never previously reported for the radiation-induced subgroup. Both tumors were characterized by next-generation sequencing and chromosomal microarray to identify potential etiologies for this response as well as to further add to the limited literature about the unique molecular profile of RIGs, showing signatures more consistent with diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype, WHO grade 4. Ultimately, we demonstrate that treatment utilizing a radiation-based regimen for GB in a previously radiated tissue can be highly successful despite historical limitations in the management of this disease.

      PMID:37025206 | PMC:PMC10070702 | DOI:10.3389/fneur.2023.1099424

      View details for PubMedID 37025206
  • Association of Pretreatment Hippocampal Volume With Neurocognitive Function in Patients Treated With Hippocampal Avoidance Whole Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology/RTOG 0933 Advances in radiation oncology
    Abraham CD, Pugh SL, Bovi JA, Gondi V, Mehta MP, Benzinger T, Owen CJ, Lo SS, Kundapur V, Brown PD, Sun AY, Howard SP, DeNittis AS, Robinson CG, Kachnic LA
    2021 Dec 11;7(6):100859. doi: 10.1016/j.adro.2021.100859. eCollection 2022 Nov-Dec.
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      PURPOSE: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933.

      METHODS AND MATERIALS: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test-Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test.

      RESULTS: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm3 (range, 1.9-7.4 cm3), 2.8 cm3 (range, 0.9-4.0 cm3), and 2.7 cm3 (range, 1.0-3.7 cm3), respectively. The median total brain volume was 1343 cm3 (range, 1120.5-1738.8 cm3). For all measures of corrected HV, increasing HV was associated with higher baseline HVLT-R TR and DR scores (ρ: range, 0.35-0.40; P-value range, .009-.024) and 4-month TR and DR scores (ρ: range, 0.29-0.40; P-value range, .009-.04), with the exception of right HV and 4-month DR scores (ρ: 0.29; P = .059). There was no significant association between HV and NCF change between baseline and 4 months. Fourteen patients (33.3%) developed NCF deterioration per the primary endpoint of RTOG 0933. There was no significant difference in HV between patients with deteriorated and nondeteriorated NCF, although in all instances, patients with deteriorated NCF had numerically lower HV.

      CONCLUSIONS: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF.

      PMID:36420209 | PMC:PMC9677217 | DOI:10.1016/j.adro.2021.100859

      View details for PubMedID 36420209
  • Entrectinib demonstrates prolonged efficacy in an adult case of radiation-refractory <em>NTRK</em> fusion glioblastoma Neuro-oncology advances
    Grogan PT, Deming DA, Helgager J, Ruszkiewicz T, Baskaya MK, Howard SP, Robins HI
    2022 Apr 13;4(1):vdac046. doi: 10.1093/noajnl/vdac046. eCollection 2022 Jan-Dec.
  • Stereotactic Radiation Therapy for an Arteriovenous Malformation of the Oral Tongue: A Teaching Case Advances in radiation oncology
    Merfeld EC, Labby ZE, Miller JR, Burr AR, Wong F, Diamond C, Wieland AR, Aagaard-Kienitz B, Howard SP
    2021 Dec 16;7(3):100870. doi: 10.1016/j.adro.2021.100870. eCollection 2022 May-Jun.
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      PMID:35079666 | PMC:PMC8777148 | DOI:10.1016/j.adro.2021.100870

      View details for PubMedID 35079666
  • Late Radiation Related Brachial Plexopathy After Pulsed Reduced Dose Rate Reirradiation of an Axillary Breast Cancer Recurrence Practical radiation oncology
    Morris BA, Burr AR, Anderson BM, Howard SP
    2021 Sep-Oct;11(5):319-322. doi: 10.1016/j.prro.2021.06.003. Epub 2021 Jun 24.
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      Radiation induced brachial plexopathy (RIBP) is an unfortunate complication of radiation involving the axilla and supraclavicular fossa. This case report highlights development of RIBP in a patient 15 years after initial radiation and 11 years after pulsed low dose rate (PRDR) re-irradiation for recurrent disease. PRDR is a radiation technique believed to lower normal tissue toxicity due to improved sublethal intrafraction damage repair of these tissues at low radiation dose rates with good reported long term locoregional control in the re-irradiation setting. However, RIBP, as seen in this patient, is a devastating side effect of high dose radiation to this region, with no effective treatment options outside of symptom management and control. In this case, the patient has remained disease free following her recurrence but has had continued RIBP with minimal improvement using pentoxyfilline for management.

      PMID:34171539 | DOI:10.1016/j.prro.2021.06.003

      View details for PubMedID 34171539
  • BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort Oncology
    Vassilakopoulou M, Won M, Curran WJ, Souhami L, Prados MD, Langer CJ, Rimm DL, Hanna JA, Neumeister VM, Melian E, Diaz AZ, Atkins JN, Komarnicky LT, Schultz CJ, Howard SP, Zhang P, Dicker AP, Knisely PS
    2021;99(9):580-588. doi: 10.1159/000516168. Epub 2021 May 6.
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      PURPOSE: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA).

      METHODS AND MATERIALS: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test.

      RESULTS: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months.

      CONCLUSIONS: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.

      PMID:33957633 | PMC:PMC8491475 | DOI:10.1159/000516168

      View details for PubMedID 33957633
  • Intranasal administration of the chemotherapeutic perillyl alcohol results in selective delivery to the cerebrospinal fluid in rats Scientific reports
    Nehra G, Andrews S, Rettig J, Gould MN, Haag JD, Howard SP, Thorne RG
    2021 Mar 18;11(1):6351. doi: 10.1038/s41598-021-85293-4.
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      Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood-brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.

      PMID:33737566 | PMC:PMC7973779 | DOI:10.1038/s41598-021-85293-4

      View details for PubMedID 33737566
  • Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma Neuro-oncology advances
    Schönthal AH, Peereboom DM, Wagle N, Lai R, Mathew AJ, Hurth KM, Simmon VF, Howard SP, Taylor LP, Chow F, Fonseca Od, Chen TC
    2021 Feb 12;3(1):vdab005. doi: 10.1093/noajnl/vdab005. eCollection 2021 Jan-Dec.
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      BACKGROUND: Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States.

      METHODS: A total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response via Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12]).

      RESULTS: Intranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived >24 months.

      CONCLUSION: Intranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM.

      PMID:33604574 | PMC:PMC7879254 | DOI:10.1093/noajnl/vdab005

      View details for PubMedID 33604574
  • Outcomes From Whole-Brain Reirradiation Using Pulsed Reduced Dose Rate Radiation Therapy Advances in radiation oncology
    Burr AR, Robins HI, Bayliss RA, Baschnagel AM, Welsh JS, Tomé WA, Howard SP
    2020 Jul 8;5(5):834-839. doi: 10.1016/j.adro.2020.06.021. eCollection 2020 Sep-Oct.
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      PURPOSE: Recurrent intracranial metastases after whole-brain irradiation pose a clinical challenge owing to the escalating morbidity associated with their treatment. Although stereotactic radiosurgery is increasingly being used, there are still situations in which whole-brain reirradiation (ReRT) continues to be appropriate. Here, we report our experience using whole-brain pulsed reduced dose rate radiation therapy (PRDR), a method that delivers radiation at a slower rate of 0.067 Gy/min to potentially increase sublethal damage repair and decrease toxicity.

      METHODS AND MATERIALS: Patients undergoing whole-brain ReRT with PRDR from January 1, 2001 to March 2019 were analyzed. The median PRDR ReRT dose was 26 Gy in 2 Gy fractions, resulting in a median total whole-brain dose of 59.5 Gy. Cox regression analysis was used for multivariate analysis. The Kaplan-Meier method was used for overall survival, progression free survival, and to evaluate the ReRT score. Binary logistic regression was employed to evaluate variables associated with rapid death.

      RESULTS: Seventy-five patients were treated with whole-brain PRDR radiation therapy. The median age was 54 (range, 26-72), the median Karnofsky performance status (KPS) was 80, and 86.7% had recursive partitioning analysis scores of 2. Thirty-two patients had over 10 metastases and 11 had leptomeningeal disease. The median overall survival was 4.1 months (range, 0.29-59.5 months) with a 1 year overall survival of 10.4%. Age, KPS, dexamethasone usage, and intracranial disease volume were significantly correlated with overall survival on multivariate analysis. A KPS ≤70 was associated with rapid death after radiation. The prognostic value of the ReRT score was validated. The most common acute toxicities were fatigue (23.1%) and headache (16.9%).

      CONCLUSIONS: In this large cohort of patients with advanced intracranial metastases, PRDR achieves acceptable survival and may decrease toxicity associated with ReRT. PRDR is an easily implemented technique and is a viable treatment option for ReRT of brain metastases.

      PMID:33083645 | PMC:PMC7557211 | DOI:10.1016/j.adro.2020.06.021

      View details for PubMedID 33083645
  • Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424 International journal of radiation oncology, biology, physics
    Fisher BJ, Pugh SL, Macdonald DR, Chakravatri A, Lesser GJ, Fox S, Rogers CL, Werner-Wasik M, Doyle T, Bahary J, Fiveash JB, Bovi JA, Howard SP, Yu HM, D'Souza D, Laack NN, Barani IJ, Kwok Y, Wahl DR, Strasser JF, Won M, Mehta MP
    2020 Jul 15;107(4):720-725. doi: 10.1016/j.ijrobp.2020.03.027. Epub 2020 Apr 3.
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      PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT).

      METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015.

      RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively.

      CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

      PMID:32251755 | PMC:PMC7456814 | DOI:10.1016/j.ijrobp.2020.03.027

      View details for PubMedID 32251755
  • The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525 Neuro-oncology practice
    Robins HI, Eickhoff J, Gilbert MR, Armstrong TS, Shi W, Groot FD, Schultz CJ, Hunter GK, Valeinis E, Roach M, Youssef EF, Souhami L, Howard SP, Lieberman FS, Herman JG, Zhang P, Mehta MP
    2019 Dec;6(6):473-478. doi: 10.1093/nop/npz006. Epub 2019 Apr 6.
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      BACKGROUND: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m2 may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m2 was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed.

      METHODS: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. Obesity was defined as a BMI ≥30.

      RESULTS: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, P < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) P = .009 in spite of the lack of association between gender and BSA or BMI.

      CONCLUSION: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.

      PMID:31832217 | PMC:PMC6899045 | DOI:10.1093/nop/npz006

      View details for PubMedID 31832217
  • Impact of adjuvant fractionated stereotactic radiotherapy dose on local control of brain metastases Journal of neuro-oncology
    Musunuru HB, Witt JS, Yadav P, Francis DM, Kuczmarska-Haas A, Labby ZE, Bassetti MF, Howard SP, Baschnagel AM
    2019 Nov;145(2):385-390. doi: 10.1007/s11060-019-03308-7. Epub 2019 Oct 12.
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      PURPOSE: The aim of this study was to determine whether a higher biological effective dose (BED) would result in improved local control in patients treated with fractionated stereotactic radiotherapy (FSRT) for their resected brain metastases.

      METHODS: Patients with newly diagnosed brain metastases without previous brain radiotherapy were retrospectively reviewed. Patients underwent surgical resection of at least one brain metastasis and were treated with adjuvant FSRT, delivering 25-36 Gy in 5-6 fractions. Outcomes were computed using Kaplan-Meier survival analysis and univariate analysis.

      RESULTS: Fifty-four patients with 63 post-operative cavities were included. Median follow-up was 16 months (3-60). Median metastasis size at diagnosis was 2.9 cm (0.6-8.1) and median planning target volume was 19.7 cm3 (6.3-68.1). Two-year local control (LC) was 83%. When stratified by dose, 2 years LC rate was 95.1% in those treated with 30-36 Gy in 5-6 fractions (BED10 of 48-57.6 Gy10) versus 59.1% lesions treated with 25 Gy in 5 fractions (BED10 of 37.5 Gy10) (p < 0.001). LC was not associated with resection cavity size. One year overall survival was 68.7%, and was independent of BED10. Symptomatic radiation necrosis occurred in 7.9% of patients and was not associated with dose.

      CONCLUSION: In the post-operative setting, high-dose FSRT (BED10 > 37.5 Gy10) were associated with a significantly higher rate of LC compared to lower BED regimens. Overall, 25 Gy in 5 fractions is not an adequate dose to control microscopic disease. If selecting a 5-fraction regimen, 30 Gy in five fractions appears to provide excellent tumor bed control.

      PMID:31606876 | DOI:10.1007/s11060-019-03308-7

      View details for PubMedID 31606876
  • Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer Practical radiation oncology
    Burr AR, Robins HI, Bayliss RA, Howard SP
    2020 Mar-Apr;10(2):e61-e70. doi: 10.1016/j.prro.2019.09.004. Epub 2019 Sep 14.
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      PURPOSE: Locoregionally recurrent breast cancer within a previously irradiated field requires weighing the benefits of reirradiation against the increased rates of toxicity. Here we evaluate the outcomes of patients treated with pulsed reduced dose rate (PRDR) radiation therapy with concurrent low-dose capecitabine as a method to increase the therapeutic ratio of re-treatment.

      METHODS AND MATERIALS: Patients treated from November 2000 to June 1, 2018 with PRDR radiation therapy at University of Wisconsin were identified. Patients were re-treated to a median dose of 54 Gy (range, 37.5-66 Gy) using PRDR radiation therapy, delivering radiation at an apparent dose rate of 6.67 cGy/min to allow for increased sublethal damage repair of normal tissues. The median cumulative dose was 109.8 Gy. Twenty-two patients were treated with concurrent capecitabine, most frequently at 500 mg twice per day. The Kaplan-Meier method was used for survival analysis, and Cox regression analysis was used for univariate and multivariate analysis.

      RESULTS: Forty-three patients were identified who underwent reirradiation for locoregionally recurrent invasive breast cancer, with a median follow-up of 20.5 months. Twenty-four patients had gross disease. Nineteen patients had simultaneous metastatic disease. The complete response rate was 83.3% in treated patients with gross disease. Locoregional recurrence-free survival was 81.3% and 73.8% for all patients at 1 and 2 years, respectively. Overall survival for patients with localized disease was 95.7% at 1 year and 91.1% at 2 years. The rate of acute grade 3 radiation dermatitis was 25.6% with no other acute grade 3 toxicities. Grade 3 late toxicity occurred in 18.6% of patients.

      CONCLUSIONS: PRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting.

      PMID:31526900 | DOI:10.1016/j.prro.2019.09.004

      View details for PubMedID 31526900
  • Large volume reirradiation after progression on bevacizumab Neuro-oncology practice
    Robins HI, Magnuson WJ, Howard SP
    2015 Dec;2(4):210. doi: 10.1093/nop/npv015. Epub 2015 Jun 23.
  • Large volume re-irradiation for recurrent meningioma with pulsed reduced dose rate radiotherapy Journal of neuro-oncology
    Witt JS, Musunuru HB, Bayliss RA, Howard SP
    2019 Jan;141(1):103-109. doi: 10.1007/s11060-018-03011-z. Epub 2018 Nov 3.
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      PURPOSE: Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether pulsed reduced dose rate radiotherapy (PRDR) was well tolerated in a small cohort of patients with recurrent meningioma.

      METHODS: We retrospectively identified eight patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Acute and late toxicities were graded based on CTCAE 4.0.

      RESULTS: Of eight patients, six had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667 Gy/min. Median time between radiation courses was 7.7 years. Median PRDR dose was 54 Gy in 27 fractions to a median volume of 261.6 cm3. Two patients (25%) had in field failure with a median follow up of 23.3 months. PFS at 6 months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥ 2 acute or late toxicities.

      CONCLUSIONS: PRDR re-irradiation was well tolerated and appeared effective for a small cohort of patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.

      PMID:30392090 | DOI:10.1007/s11060-018-03011-z

      View details for PubMedID 30392090
  • Radiation treatment planning and delivery strategies for a pregnant brain tumor patient Journal of applied clinical medical physics
    Labby ZE, Barraclough B, Bayliss RA, Besemer AE, Dunkerley AP, Howard SP
    2018 Sep;19(5):368-374. doi: 10.1002/acm2.12262. Epub 2018 Jul 30.
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      The management of a pregnant patient in radiation oncology is an infrequent event requiring careful consideration by both the physician and physicist. The aim of this manuscript was to highlight treatment planning techniques and detail measurements of fetal dose for a pregnant patient recently requiring treatment for a brain cancer. A 27-year-old woman was treated during gestational weeks 19-25 for a resected grade 3 astrocytoma to 50.4 Gy in 28 fractions, followed by an additional 9 Gy boost in five fractions. Four potential plans were developed for the patient: a 6 MV 3D-conformal treatment plan with enhanced dynamic wedges, a 6 MV step-and-shoot (SnS) intensity-modulated radiation therapy (IMRT) plan, an unflattened 6 MV SnS IMRT plan, and an Accuray TomoTherapy HDA helical IMRT treatment plan. All treatment plans used strategies to reduce peripheral dose. Fetal dose was estimated for each treatment plan using available literature references, and measurements were made using thermoluminescent dosimeters (TLDs) and an ionization chamber with an anthropomorphic phantom. TLD measurements from a full-course radiation delivery ranged from 1.0 to 1.6 cGy for the 3D-conformal treatment plan, from 1.0 to 1.5 cGy for the 6 MV SnS IMRT plan, from 0.6 to 1.0 cGy for the unflattened 6 MV SnS IMRT plan, and from 1.9 to 2.6 cGy for the TomoTherapy treatment plan. The unflattened 6 MV SnS IMRT treatment plan was selected for treatment for this particular patient, though the fetal doses from all treatment plans were deemed acceptable. The cumulative dose to the patient's unshielded fetus is estimated to be 1.0 cGy at most. The planning technique and distance between the treatment target and fetus both contributed to this relatively low fetal dose. Relevant treatment planning strategies and treatment delivery considerations are discussed to aid radiation oncologists and medical physicists in the management of pregnant patients.

      PMID:30062720 | PMC:PMC6123144 | DOI:10.1002/acm2.12262

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  • Bone marrow suppression as a complication of total skin helical tomotherapy in the treatment of mycosis fungoides Radiation oncology (London, England)
    Schaff EM, Rosenberg SA, Olson SJ, Howard SP, Bradley KA
    2018 Apr 13;13(1):67. doi: 10.1186/s13014-018-1013-2.
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      BACKGROUND: Total skin electron beam therapy (TSEBT) is an effective treatment in mycosis fungoides. Total skin helical tomotherapy (TSHT) may be an alternative to TSEBT and may offer several dosimetric and treatment advantages. There are currently very few published treatment results using TSHT in place of TSEBT for treatment of mycosis fungoides.

      CASE PRESENTATION: Two patients with mycosis fungoides were treated at our institution using TSHT. The first patient was a 69-year-old Caucasian female with stage IVA2 (T2 N3 M0 B2) disease who was treated to a dose of 12 Gy in 8 fractions, with a bone marrow mean dose of 1.66 Gy and V10 = 0.41%. Two weeks after ending treatment the patient developed myelosuppression including grade 4 thrombocytopenia and required blood and platelet transfusions. The second patient was a 29-year-old Caucasian female with stage I (T2 N0 M0 B0) disease. This patient previously had been treated for mycosis fungoides using helical tomotherapy (HT) at a dose of 20 Gy to a localized region and experienced mild thrombocytopenia at that time. The patient then underwent retreatment 17 months later with TSHT to a dose of 12 Gy in 6 fractions with a mean bone marrow dose of 2.3 Gy and V10 = 4.28%. This patient once again experienced myelosuppression that included grade 4 thrombocytopenia. She also required blood and platelet transfusions.

      CONCLUSIONS: Both patients treated with TSHT experienced severe bone marrow suppression including grade 4 thrombocytopenia. This was more severe than expected considering the relatively low overall prescription dose and despite a planning constraint placed on the bone marrow of a mean dose of < 2 Gy. These outcomes suggest that patients treated using TSHT should be closely monitored for myelosuppression and caution used even when treating to a dose of 12 Gy.

      PMID:29653544 | PMC:PMC5899362 | DOI:10.1186/s13014-018-1013-2

      View details for PubMedID 29653544
  • Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: a secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database Neuro-oncology
    Blumenthal DT, Won M, Mehta MP, Gilbert MR, Brown PD, Bokstein F, Brachman DG, Werner-Wasik M, Hunter GK, Valeinis E, Hopkins K, Souhami L, Howard SP, Lieberman FS, Shrieve DC, Wendland MM, Robinson CG, Zhang P, Corn BW
    2018 Jun 18;20(7):966-974. doi: 10.1093/neuonc/noy017.
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      BACKGROUND: We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant.

      METHODS: Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test.

      RESULTS: Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63).

      CONCLUSIONS: We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

      PMID:29462493 | PMC:PMC6007748 | DOI:10.1093/neuonc/noy017

      View details for PubMedID 29462493
  • Primary intracranial leiomyosarcoma in an immunocompetent patient: Case report and review of the literature Clinical neurology and neurosurgery
    Gallagher SJ, Rosenberg SA, Francis D, Salamat S, Howard SP, Kimple RJ
    2018 Feb;165:76-80. doi: 10.1016/j.clineuro.2017.12.014. Epub 2018 Jan 6.
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      Primary leiomyosarcoma is a rare tumor in the CNS, with few reported cases. Here, we describe a case of a primary intracranial leiomyosarcoma of the tentorium cerebelli. A 43-year-old woman presented with headache, acute vision loss, and difficulty speaking. MRI revealed a large heterogeneous-enhancing occipital mass, which was subsequently resected and diagnosed as a primary intracranial leiomyosarcoma. The patient went onto adjuvant radiotherapy delivering 60 Gy in 30 fractions. These tumors are exceedingly rare in immunocompetent individuals. We reviewed the 16 cases that have been reported in the literature. Surgical resection was the most common treatment (92%) with 53% receiving adjuvant radiation. There currently is no standard treatment regimen for intracranial leiomyosarcomas. Additional case reports that include descriptive treatment approaches with patient outcomes may help ascertain the best approach to treating these malignancies.

      PMID:29324399 | DOI:10.1016/j.clineuro.2017.12.014

      View details for PubMedID 29324399
  • Familial Trigeminal Neuralgia Treated with Stereotactic Radiosurgery: A Case Report and Literature Review Journal of radiation oncology
    Denu RA, Rosenberg SA, Howard SP
    2017 Jun;6(2):149-152. doi: 10.1007/s13566-017-0300-0. Epub 2017 Mar 20.
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      BACKGROUND: Trigeminal neuralgia (TN) is a chronic pain condition characterized by brief episodes of lancinating pain in one or more distributions of the trigeminal nerve. Episodes of pain secondary to TN are triggered by certain stimuli, such as chewing, shaving, or touching the face. Although a common cause of TN is compression of the trigeminal nerve root entry zone by an artery or vein, many cases of TN are idiopathic. However, there have been limited reports in the literature of familial TN.

      CASE PRESENTATION: A 31-year-old male presented with classic TN symptoms in the right V1/V2 distribution that recently progressed to the V3 distribution a case of familial TN. His father an brother both have TN. Carbamazepine, oxcarbazepine, and rhizotomy did not improve his symptoms. He was treated with stereotactic radiosurgery (SRS) with a dose of 85 Gy delivered to the proximal trigeminal root with improvement in his pain. We also review and summarize the over 160 cases of familial TN found in the literature.

      CONCLUSIONS: This is the first reported case of familial TN treated with SRS. Patients with familial TN are more likely to have bilateral disease, to present with earlier onset, and to become refractory to medical therapy and may require more aggressive approaches. We propose that SRS is a good treatment approach for these patients.

      PMID:29201285 | PMC:PMC5705085 | DOI:10.1007/s13566-017-0300-0

      View details for PubMedID 29201285
  • Investigating the Effect of Reirradiation or Systemic Therapy in Patients With Glioblastoma After Tumor Progression: A Secondary Analysis of NRG Oncology/Radiation Therapy Oncology Group Trial 0525 International journal of radiation oncology, biology, physics
    Shi W, Bryan MS, Gilbert MR, Mehta MP, Blumenthal DT, Brown PD, Valeinis E, Hopkins K, Souhami L, Andrews DW, Tzuk-Shina T, Howard SP, Youssef EF, Lessard N, Dignam JJ, Werner-Wasik M
    2018 Jan 1;100(1):38-44. doi: 10.1016/j.ijrobp.2017.08.038. Epub 2017 Sep 4.
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      PURPOSE: To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma.

      METHODS AND MATERIALS: This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders.

      RESULTS: The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone).

      CONCLUSIONS: Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

      PMID:29102648 | PMC:PMC5742545 | DOI:10.1016/j.ijrobp.2017.08.038

      View details for PubMedID 29102648
  • The evolving role for re-irradiation in the management of recurrent grade 4 glioma Journal of neuro-oncology
    Howard SP, Krauze A, Chan MD, Tsien C, Tomé WA
    2017 Sep;134(3):523-530. doi: 10.1007/s11060-017-2392-1. Epub 2017 Apr 6.
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      Although significant gains have been realized in the management of grade 4 glioma, the majority of these patients will ultimately suffer local recurrence within the prior field of treatment. Clearly, novel local treatment strategies are required to improve patient outcomes. Concerns of toxicity have limited enthusiasm for the utilization of re-irradiation as a treatment option. However, using modern imaging technology and precision radiotherapy delivery techniques re-irradiation has proven a feasible option achieving both a palliative benefit and prolongation of survival with low toxicity rates. The evolution of re-irradiation as a treatment modality for recurrent grade 4 glioma is reviewed. In addition, potential targeted radiosensitizers to be used in conjunction with re-irradiation are also discussed.

      PMID:28386661 | DOI:10.1007/s11060-017-2392-1

      View details for PubMedID 28386661
  • Karenitecin (bnp1350) and flavopridol as radiosensitizers in malignant glioma Journal of neurology & neuromedicine
    Rajesh D, Robins HI, Howard SP
    2016;1(6):1-10. doi: 10.29245/2572.942x/2016/6.1061.
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      The poor prognosis of malignant glioma patients highlights the need to develop low toxicity, tumor specific agents with the ability to synergize with proven efficacious treatment modalities, e.g., ionizing irradiation. This paper investigates the potential of BNP1350 (karenitecin), a topoisomerase I-targeting anticancer agent, and flavopridol a cyclin-dependent kinase inhibitor as radiosensitizers at clinically relevant doses in glioblastoma cell lines. A clonogenic survival and apoptosis assays were performed to test the effect of karenitecin (0.1 nM to 10 nM), flavopridol, (50 nM to 500 nM), radiation (1 Gy to 5.5 Gy) and a combination of radiation and karenitecin or radiation and flavopridol on the glioma cell lines T986 and M059K. Cells were stained for cyclins B and D using antibodies followed by flow cytometry. Propidium Iodide staining was used to reveal the various phases of the cell cycle; cyclin staining in the G0/G1 and G2/M phase of the cell cycle was estimated as the Mean Fluorescence Intensity (MFI) after subtracting the MFI recorded by the isotype controls. Results demonstrated that in irradiated cells, pretreatment with karenitecin induced apoptosis, a transient arrest in the G2/M phase of the cell cycle and increased the expression of cyclin B1. Flavopridol treatment also induced apoptosis and a transient block in the G2/M phase of the cell cycle. The combined effects of karenitecin and flavopridol displayed synergistic effects. The unique radiosensitizing activity of orally administrable karenitecin and flavopridol is consistent with continued investigation of these compounds preclinically, as well as in the clinical setting.

      PMID:28111642 | PMC:PMC5243123 | DOI:10.29245/2572.942x/2016/6.1061

      View details for PubMedID 28111642
  • Comment on "A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression" Journal of immunology (Baltimore, Md. : 1950)
    Welsh JS, Howard SP
    2015 Oct 15;195(8):3505. doi: 10.4049/jimmunol.1501667.
  • Persistent Activation of the Innate Immune Response in Adult Drosophila Following Radiation Exposure During Larval Development G3 (Bethesda, Md.)
    Sudmeier LJ, Samudrala S, Howard SP, Ganetzky B
    2015 Sep 1;5(11):2299-306. doi: 10.1534/g3.115.021782.
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      Cranial radiation therapy (CRT) is an effective treatment for pediatric central nervous system malignancies, but survivors often suffer from neurological and neurocognitive side effects that occur many years after radiation exposure. Although the biological mechanisms underlying these deleterious side effects are incompletely understood, radiation exposure triggers an acute inflammatory response that may evolve into chronic inflammation, offering one avenue of investigation. Recently, we developed a Drosophila model of the neurotoxic side effects of radiation exposure. Here we use this model to investigate the role of the innate immune system in response to radiation exposure. We show that the innate immune response and NF-ĸB target gene expression is activated in the adult Drosophila brain following radiation exposure during larval development, and that this response is sustained in adult flies weeks after radiation exposure. We also present preliminary data suggesting that innate immunity is radioprotective during Drosophila development. Together our data suggest that activation of the innate immune response may be beneficial initially for survival following radiation exposure but result in long-term deleterious consequences, with chronic inflammation leading to impaired neuronal function and viability at later stages. This work lays the foundation for future studies of how the innate immune response is triggered by radiation exposure and its role in mediating the biological responses to radiation. These studies may facilitate the development of strategies to reduce the deleterious side effects of CRT.

      PMID:26333838 | PMC:PMC4632050 | DOI:10.1534/g3.115.021782

      View details for PubMedID 26333838
  • A Drosophila model to investigate the neurotoxic side effects of radiation exposure Disease models & mechanisms
    Sudmeier LJ, Howard SP, Ganetzky B
    2015 Jul 1;8(7):669-77. doi: 10.1242/dmm.019786.
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      Children undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. Wild-type third-instar larvae were irradiated with single doses of γ-radiation, and the percentage that survived to adulthood was determined. Motor function of surviving adults was examined with a climbing assay, and longevity was assessed by measuring lifespan. Neuronal cell death was assayed by using immunohistochemistry in adult brains. We also tested the sensitivity at different developmental stages by irradiating larvae at various time points. Irradiating late third-instar larvae at a dose of 20 Gy or higher impaired the motor activity of surviving adults. A dose of 40 Gy or higher resulted in a precipitous reduction in the percentage of larvae that survive to adulthood. A dose-dependent decrease in adult longevity was paralleled by a dose-dependent increase in activated Death caspase-1 (Dcp1) in adult brains. Survival to adulthood and adult lifespan were more severely impaired with decreasing larval age at the time of irradiation. Our initial survey of the Drosophila Genetic Reference Panel demonstrated that differences in genotype can confer phenotypic differences in radio-sensitivity for developmental survival and motor function. This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions.

      PMID:26092528 | PMC:PMC4486860 | DOI:10.1242/dmm.019786

      View details for PubMedID 26092528
  • Wide-field pulsed reduced dose rate radiotherapy (PRDR) for recurrent ependymoma in pediatric and young adult patients Anticancer research
    Mohindra P, Robins HI, Tomé WA, Hayes L, Howard SP
    2013 Jun;33(6):2611-8.
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      AIM: This retrospective analysis evaluates feasibility of wide-field re-irradiation using pulsed reduced dose rate (PRDR) technique in patients with recurrent ependymoma. PRDR employs a dose rate of 6 cGy/min, as opposed to 400-600 cGy/min for conventional radiation, allowing for enhanced normal tissue repair.

      PATIENTS AND METHODS: Five patients with recurrent ependymoma having eight lesions (two brain, six spinal cord) were treated with PRDR. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan Meier method.

      RESULTS: The median interval between two radiation courses was 58 months (range: 32-212 months). The median PRDR dose was 40 Gy (range: 30.6-54 Gy) with a median cumulative lifetime dose of 105.2 Gy (range: 90-162.4 Gy). At a median post-PRDR follow-up of 64 months, estimated 4-year OS and PFS from PRDR was 60% and 35.7%, respectively. None of the patients developed necrosis on serial magnetic resonance imaging scans, and only one patient had progressive mild radiculopathy.

      CONCLUSION: In patients with large-volume recurrent ependymoma, re-irradiation with wide-field PRDR is a feasible option.


      View details for PubMedID 23749916
  • Treatment planning for pulsed reduced dose-rate radiotherapy in helical tomotherapy International journal of radiation oncology, biology, physics
    Rong Y, Paliwal B, Howard SP, Welsh J
    2011 Mar 1;79(3):934-42. doi: 10.1016/j.ijrobp.2010.05.055. Epub 2010 Sep 29.
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      PURPOSE: Pulsed reduced dose-rate radiotherapy (PRDR) is a valuable method of reirradiation because of its potential to reduce late normal tissue toxicity while still yielding significant tumoricidal effect. A typical method using a conventional linear accelerator (linac) is to deliver a series of 20-cGy pulses separated by 3-min intervals to give an effective dose-rate of just under 7 cGy/min. Such a strategy is fraught with difficulties when attempted on a helical tomotherapy unit. We investigated various means to overcome this limitation.

      METHODS AND MATERIALS: Phantom and patient cases were studied. Plans were generated with varying combinations of field width (FW), pitch, and modulation factor (MF) to administer 200 cGy per fraction to the planning target in eight subfractions, thereby mimicking the technique used on conventional linacs. Plans were compared using dose-volume histograms, homogeneity indices, conformation numbers, and treatment time. Plan delivery quality assurance was performed to assess deliverability.

      RESULTS: It was observed that for helical tomotherapy, intrinsic limitations in leaf open time in the multileaf collimator deteriorate plan quality and deliverability substantially when attempting to deliver very low doses such as 20-40 cGy. The various permutations evaluated revealed that the combination of small FW (1.0 cm), small MF (1.3-1.5), and large pitch (∼0.86), along with the half-gantry-angle-blocked scheme, can generate clinically acceptable plans with acceptable delivery accuracy (±3%).

      CONCLUSION: Pulsed reduced dose-rate radiotherapy can be accurately delivered using helical tomotherapy for tumor reirradiation when the appropriate combination of FW, MF, and pitch is used.

      PMID:20884127 | DOI:10.1016/j.ijrobp.2010.05.055

      View details for PubMedID 20884127
  • Reirradiation of glioblastoma through the use of a reduced dose rate on a tomotherapy unit Technology in cancer research & treatment
    Rasmussen KH, Hardcastle N, Howard SP, Tomé WA
    2010 Aug;9(4):399-406. doi: 10.1177/153303461000900409.
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      Pulsed Reduced Dose Rate (PRDR) is a method of irradiation designed to minimize radiation-related toxicities in patients undergoing reirradiation for loco-regional reoccurrence of glioblastoma. PRDR delivers a standard 2 Gy fraction delivered on a conventional medical linear accelerator using conventional 3D conformal beam arrangements. To reduce the likelihood of normal tissue complications, radiation is delivered over ten 0.2 Gy sub-fractions with a 3 minute time interval between subfractions to give a maximal time averaged dose rate of 4 Gy/hr. However, a TomoTherapy unit has a fixed output rate of 8 Gy/min. If the dose per fraction is conventionally planned at less than 0.6 Gy/fraction, the result is a clinically unacceptable treatment plan. The method described in this paper involves a virtual grid style blocking scheme, where half of the beam angles are directionally blocked using 15 equally spaced segments surrounding the center of the image set. Ten patients treated using conventional PRDR with an average PTV volume of 353.3 ml were retrospectively re-planned using five techniques (standard 2 Gy fraction, 2 Gy in ten 0.2 Gy fractions without grid blocking, two grid patterns, and a combination plan incorporating both grids) and analyzed with conformation numbers (CN), homogeneity indexes (HI), and dose volumes to normal tissues. Plans were optimized using equal constraints and machine parameters. The grid method allowed for clinically acceptable treatment plans at 0.2 Gy with a treatment time < or = 3 min per subfraction. The average HI was slightly poorer for the combination plan versus the standard 2 Gy fraction plan (0.064 versus 0.027) and the CN was similar over all techniques (0.72 - 0.73) employed. Normal tissue dose volumes for each patient were also similar for each technique. Initial ion chamber measurements agree with predicted values for a 0.2 Gy subfraction. PRDR is deliverable on a TomoTherapy system using our virtual directional blocking method. Results can be slightly improved through the use of two grids alternated on a daily basis. The dose to normal structures for individual patients was similar for all methods.

      PMID:20626205 | PMC:PMC2906824 | DOI:10.1177/153303461000900409

      View details for PubMedID 20626205
  • Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate radiotherapy International journal of radiation oncology, biology, physics
    Adkison JB, Tomé W, Seo S, Richards GM, Robins HI, Rassmussen K, Welsh JS, Mahler PA, Howard SP
    2011 Mar 1;79(3):835-41. doi: 10.1016/j.ijrobp.2009.11.058. Epub 2010 May 14.
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      PURPOSE: Pulsed reduced-dose-rate radiotherapy (PRDR) is a reirradiation technique that reduces the effective dose rate and increases the treatment time, allowing sublethal damage repair during irradiation.

      PATIENTS AND METHODS: A total of 103 patients with recurrent glioma underwent reirradiation using PRDR (86 considered to have Grade 4 at PRDR). PRDR was delivered using a series of 0.2-Gy pulses at 3-min intervals, creating an apparent dose rate of 0.0667 Gy/min to a median dose of 50 Gy (range, 20-60) delivered in 1.8-2.0-Gy fractions. The mean treatment volume was 403.5±189.4 cm3 according to T2-weighted magnetic resonance imaging and a 2-cm margin.

      RESULTS: For the initial or upgraded Grade 4 cohort (n=86), the median interval from the first irradiation to PRDR was 14 months. Patients undergoing PRDR within 14 months of the first irradiation (n=43) had a median survival of 21 weeks. Those treated ≥14 months after radiotherapy had a median survival of 28 weeks (n=43; p=0.004 and HR=1.82 with a 95% CI ranging from 1.25 to 3.10). These data compared favorably to historical data sets, because only 16% of the patients were treated at first relapse (with 46% treated at the second relapse, 32% at the third or fourth relapse, and 4% at the fourth or fifth relapse). The median survival since diagnosis and retreatment was 6.3 years and 11.4 months for low-grade, 4.1 years and 5.6 months for Grade 3, and 1.6 years and 5.1 months for Grade 4 tumors, respectively, according to the initial histologic findings. Multivariate analysis revealed age at the initial diagnosis, initial low-grade disease, and Karnofsky performance score of ≥80 to be significant predictors of survival after initiation of PRDR.

      CONCLUSION: PRDR allowed for safe retreatment of larger volumes to high doses with palliative benefit.

      PMID:20472350 | DOI:10.1016/j.ijrobp.2009.11.058

      View details for PubMedID 20472350
  • Pulsed reduced dose-rate radiotherapy: a novel locoregional retreatment strategy for breast cancer recurrence in the previously irradiated chest wall, axilla, or supraclavicular region Breast cancer research and treatment
    Richards GM, Tomé WA, Robins HI, Stewart JA, Welsh JS, Mahler PA, Howard SP
    2009 Mar;114(2):307-13. doi: 10.1007/s10549-008-9995-3. Epub 2008 Apr 4.
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      PURPOSE: Reirradiation of breast cancer locoregional recurrence (LRR) in the setting of prior post-mastectomy radiation poses a significant clinical challenge due to the high risk for severe toxicity. In an attempt to reduce these toxicities, we have developed pulsed reduced dose-rate radiotherapy (PRDR), a reirradiation technique in which a series of 0.2 Gy pulses separated by 3-min time intervals is delivered, creating an apparent dose rate of 0.0667 Gy/min. Here we describe our early experience with PRDR.

      PATIENTS AND METHODS: We reirradiated 17 patients with LRR breast cancer to the chest wall, axilla, or supraclavicular region using PRDR. The median prior radiation dose was 60 Gy. We delivered a median PRDR dose of 54 Gy (range 40-66 Gy) in 1.8-2.0 Gy per fraction. Eight patients received concomitant low dose capecitabine for radiosensitization. The median treatment volume was 2,084 cm(3) (range 843-7,881 cm(3)).

      RESULTS: At a median follow-up of 18 months (range 4-75 months) only 2 patients have had tumor failure in the treatment region. Estimated 2-year local control rate is 92%. Treatment was well tolerated with 4 patients experiencing grade 3 acute skin toxicity. Despite a median cumulative dose of 110 Gy (range 80-236 Gy), there has been only one grade 3 and one grade 4 late toxicity.

      CONCLUSIONS: With a median follow-up of 18 months, PRDR appears to be an effective method to reirradiate large volumes of previously irradiated tissue in selected patients with locoregional chest wall, axilla, and supraclavicular recurrences.

      PMID:18389365 | DOI:10.1007/s10549-008-9995-3

      View details for PubMedID 18389365
  • Systemic iodine 125 activity after GliaSite brachytherapy: safety considerations Brachytherapy
    Adkison JB, Thomadsen B, Howard SP
    2008 Jan-Mar;7(1):43-6. doi: 10.1016/j.brachy.2007.11.001. Epub 2008 Jan 16.
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      PURPOSE: After contaminated radioactive linens were detected on the completion of intracranial brachytherapy for a patient episodically incontinent of urine, the systemic absorption of iodine 125 from the GliaSite Radiation Therapy System was studied. Diffusion and leakage of (125)I through the walls of the GliaSite balloon catheter have previously been reported to be negligible in both animal and human studies examining the radioactivity of urine during and after treatment. Our study estimated total systemic absorption based on activity defect measurements rather than using urinary excretion as a surrogate.

      METHODS AND MATERIALS: Six patients treated with complete data were reviewed. The activity at the time of injection was compared to the activity recovered on completion of treatment after adjustment for decay.

      RESULTS: By comparing the activity of (125)I infused with the activity recovered, 0.5-5.5% of infused (125)I remained unaccounted after adjusting for decay over the 4-day treatment period. The patient with contaminated hospital linens due to urinary incontinence had unaccounted activity of 2.3%. Comparisons of the volume of liquid (125)I and saline removed on completion to treatment to the volume originally instilled revealed no difference using hand-held syringes.

      CONCLUSIONS: The systemic absorption of (125)I is much greater than previously appreciated with potential clinical sequelae and safety concerns. GliaSite should be used with caution in patients incontinent of urine, and a Foley catheter should be placed to collect contaminated urine for incontinent patients.

      PMID:18201938 | DOI:10.1016/j.brachy.2007.11.001

      View details for PubMedID 18201938
  • Pulsed reduced dose-rate radiotherapy: case report : a novel re-treatment strategy in the management of recurrent glioblastoma multiforme Journal of neuro-oncology
    Cannon GM, Tomé WA, Robins HI, Howard SP
    2007 Jul;83(3):307-11. doi: 10.1007/s11060-007-9329-z. Epub 2007 Jan 25.
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      The initial management of malignant gliomas is multimodality in nature, consisting of surgery, radiation therapy and chemotherapy. However, once progression has occurred, treatment options are limited both in terms of selection and efficacy. We report a case of a 37 year-old male diagnosed with a Grade II astrocytoma initially treated with surgery and external beam radiation therapy consisting of 54 Gy delivered in 1.8 Gy fractions that subsequently progressed to a Grade IV astrocytoma. This was managed with temozolomide chemotherapy until the patient exhibited further progression. Although the patient had received prior full dose radiotherapy, he was re-treated with external beam radiotherapy delivered at a substantially reduced dose-rate. This reduction in dose-rate is obtained by delivering treatment in a series of 0.2 Gy pulses separated by 3 min time intervals, creating an apparent dose rate of 0.0667 Gy/min. The region of recurrence was treated to a dose of 50 Gy delivered using 25 daily fractions of 2.0 Gy. The patient had both a radiographic response and clinical improvement following re-irradiation using pulsed reduced dose-rate radiotherapy with no apparent acute or late neurologic toxicities at a time when other treatment options were not available. Despite delivering 104 Gy to the tumor bed and the surrounding brain parenchyma, at no time was there radiographic evidence of radiation-induced normal tissue necrosis. The radiobiologic basis for the use of pulsed reduced dose-rate external beam radiotherapy in the management of recurrent glioma patients is discussed.

      PMID:17252184 | DOI:10.1007/s11060-007-9329-z

      View details for PubMedID 17252184
  • On the possible increase in local tumour control probability for gliomas exhibiting low dose hyper-radiosensitivity using a pulsed schedule The British journal of radiology
    Tomé WA, Howard SP
    2007 Jan;80(949):32-7. doi: 10.1259/bjr/15764945. Epub 2006 Aug 31.
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      Using modelling, we have developed a treatment strategy for gliomas exhibiting low dose hyper-radiosensitivity (HRS) that employs both a reduced dose-rate and pulsed treatment dose delivery. The model exploits the low dose hypersensitivity observed in some glioma cell lines at low radiation doses. We show, based on in vitro data, that a pulsed delivery of external beam radiation therapy could yield significant increases in local control. We therefore propose a pulsed delivery scheme for the treatment of gliomas in which the daily treatment fraction is delivered using 0.20 Gy pulses, separated by three minutes for a time-averaged dose-rate of 0.0667 Gy/min. The dose per pulse of 0.2 Gy is near or below the transition dose observed in vitro for four of the five glioma cell lines we have studied. Using five established glioma cell lines our modelling demonstrates that our pulsed delivery scheme yields a substantial increase in tumour control probability (TCP).

      PMID:16945935 | DOI:10.1259/bjr/15764945

      View details for PubMedID 16945935
  • Motexafin-gadolinium taken up in vitro by at least 90% of glioblastoma cell nuclei Clinical cancer research : an official journal of the American Association for Cancer Research
    Stasio GD, Rajesh D, Ford JM, Daniels MJ, Erhardt RJ, Frazer BH, Tyliszczak T, Gilles MK, Conhaim RL, Howard SP, Fowler JF, Estève F, Mehta MP
    2006 Jan 1;12(1):206-13. doi: 10.1158/1078-0432.CCR-05-0743.
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      PURPOSE: We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the future development of radiosensitizing techniques, such as gadolinium synchrotron stereotactic radiotherapy (GdSSR), a new putative treatment for glioblastoma multiforme.

      EXPERIMENTAL DESIGN: In this approach, administration of a tumor-seeking Gd-containing compound would be followed by stereotactic external beam radiotherapy with 51-keV photons from a synchrotron source. At least two criteria must be satisfied before this therapy can be established: Gd must accumulate in cancer cells and spare the normal tissue; Gd must be present in almost all the cancer cell nuclei. We address the in vitro intranuclear uptake of motexafin gadolinium in this article. We analyzed the Gd distribution with subcellular resolution in four human glioblastoma cell lines, using three independent methods: two novel synchrotron spectromicroscopic techniques and one confocal microscopy. We present in vitro evidence that the majority of the cell nuclei take up motexafin gadolinium, a drug that is known to selectively reach glioblastoma multiforme.

      RESULTS: With all three methods, we found Gd in at least 90% of the cell nuclei. The results are highly reproducible across different cell lines. The present data provide evidence for further studies, with the goal of developing GdSSR, a process that will require further in vivo animal and future clinical studies.

      PMID:16397044 | DOI:10.1158/1078-0432.CCR-05-0743

      View details for PubMedID 16397044
  • Sm-153 EDTMP for recurrent metastatic osteosarcoma Clinical advances in hematology & oncology : H&O
    Welsh JS, Thurman SA, Borzillary S, Schwartz CL, Howard SP
    2003 Mar;1(3):181-3; discussion 183.
  • Are gadolinium contrast agents suitable for gadolinium neutron capture therapy? Neurological research
    Stasio GD, Rajesh D, Casalbore P, Daniels MJ, Erhardt RJ, Frazer BH, Wiese LM, Richter KL, Sonderegger BR, Gilbert B, Schaub S, Cannara RJ, Crawford JF, Gilles MK, Tyliszczak T, Fowler JF, Larocca LM, Howard SP, Mercanti D, Mehta MP, Pallini R
    2005 Jun;27(4):387-98. doi: 10.1179/016164105X17206.
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      OBJECTIVE: Gadolinium neutron capture therapy (GdNCT) is a potential treatment for malignant tumors based on two steps: (1) injection of a tumor-specific (157)Gd compound; (2) tumor irradiation with thermal neutrons. The GdNC reaction can induce cell death provided that Gd is proximate to DNA. Here, we studied the nuclear uptake of Gd by glioblastoma (GBM) tumor cells after treatment with two Gd compounds commonly used for magnetic resonance imaging, to evaluate their potential as GdNCT agents.

      METHODS: Using synchrotron X-ray spectromicroscopy, we analyzed the Gd distribution at the subcellular level in: (1) human cultured GBM cells exposed to Gd-DTPA or Gd-DOTA for 0-72 hours; (2) intracerebrally implanted C6 glioma tumors in rats injected with one or two doses of Gd-DOTA, and (3) tumor samples from GBM patients injected with Gd-DTPA.

      RESULTS: In cell cultures, Gd-DTPA and Gd-DOTA were found in 84% and 56% of the cell nuclei, respectively. In rat tumors, Gd penetrated the nuclei of 47% and 85% of the tumor cells, after single and double injection of Gd-DOTA, respectively. In contrast, in human GBM tumors 6.1% of the cell nuclei contained Gd-DTPA.

      DISCUSSION: Efficacy of Gd-DTPA and Gd-DOTA as GdNCT agents is predicted to be low, due to the insufficient number of tumor cell nuclei incorporating Gd. Although multiple administration schedules in vivo might induce Gd penetration into more tumor cell nuclei, a search for new Gd compounds with higher nuclear affinity is warranted before planning GdNCT in animal models or clinical trials.

      PMID:15949236 | DOI:10.1179/016164105X17206

      View details for PubMedID 15949236
  • Thymoma and multiple malignancies: a case of five synchronous neoplasms and literature review Clinical medicine & research
    Welsh JS, Thurman SA, Howard SP
    2003 Jul;1(3):227-32. doi: 10.3121/cmr.1.3.227.
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      The presence of five discrete synchronous or metachronous primary neoplasms in a single patient is an extremely rare event. This is a report of a patient with a malignant (invasive) thymoma and four other independent primary neoplasms including: gliosarcoma, papillary thyroid cancer, meningioma and metastatic adenocarcinoma of the colon, found synchronously at autopsy. Thymoma patients appear to have an inherent predisposition towards developing additional neoplasms. Other than the thymoma, the presented patient had no obvious risk factors for neoplasia. This case provides evidence for an unusual syndrome of thymoma and multiple primary neoplasms. Further research is required to elucidate the mechanism of this association. Meanwhile, heightened awareness of this association may allow earlier detection and treatment of additional cancers in patients with a history of thymoma.

      PMID:15931312 | PMC:PMC1069048 | DOI:10.3121/cmr.1.3.227

      View details for PubMedID 15931312
  • Precautions in the use of intensity-modulated radiation therapy Technology in cancer research & treatment
    Welsh JS, Limmer JP, Howard SP, Diamond D, Harari PM, Tome W
    2005 Apr;4(2):203-10. doi: 10.1177/153303460500400209.
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      Intensity-modulated radiation therapy (IMRT) represents a significant technological advancement in the ability to deliver highly conformal radiation therapy. Thanks to increased availability, general clinical implementation has become progressively more common. However, there are several precautions worthy of comment regarding the clinical applications of IMRT. In theory, the increased irradiated volume and leakage radiation that occasionally accompanies IMRT could contribute to unanticipated complications and safety concerns. The protracted delivery time of IMRT with the associated increased linac monitor units can result in photoactivation of elements within the linac collimator, thereby inadvertently increasing radiation exposure to patients and staff when high-energy photons are used. The increased volumes of normal tissue exposed to lower doses of radiation through IMRT theoretically could promote carcinogenesis and complications due to the bystander effect, low-dose hyper-radiosensitivity, and diminished repair of double strand DNA breaks at very low doses. Tumor control may be adversely affected by the lower radiation dose-rates of delivery sometimes associated with IMRT as well the occasionally seen low dose "cold shoulder" on the dose-volume histograms. Unusual clinical reactions can appear as a result of the complex, unfamiliar dose-distributions occasionally generated by IMRT treatment planning. Here we discuss some of the precautions worthy of consideration when using IMRT and how these might be addressed in routine practice.

      PMID:15773789 | DOI:10.1177/153303460500400209

      View details for PubMedID 15773789
  • Non-Hodgkin's lymphoma presenting as a pelvic mass with elevated CA-125 Gynecologic oncology
    Allen GW, Forouzannia A, Bailey HH, Howard SP
    2004 Sep;94(3):811-3. doi: 10.1016/j.ygyno.2004.05.057.
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      BACKGROUND: We report a case of pelvic lymphoma with an elevated serum CA-125 level, initially misdiagnosed as ovarian carcinoma. A review of the literature is presented and a possible mechanism for CA-125 elevation in diseases other than ovarian cancer is discussed.

      CASE: A 50-year-old woman presented with symptoms of progressive dyspnea, early satiety, fatigue, and weight loss. Workup revealed a pelvic mass and an elevated CA-125 level. Paclitaxel and carboplatin were administered to facilitate therapy and provide symptomatic relief for a presumed bulky ovarian carcinoma. A biopsy was obtained after the initiation of chemotherapy, yielding the diagnosis of diffuse large B cell non-Hodgkin's lymphoma, stage II-B. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by radiotherapy resulted in long-term disease remission. A search of the literature revealed several clinical series describing the elevation of CA-125 in a variety of diseases, both benign and malignant.

      CONCLUSIONS: In the setting of a newly diagnosed pelvic mass, care should be taken when interpreting an elevated CA-125 level. While ovarian cancer is high on the list of differential diagnoses, lymphoma cannot be excluded until a tissue diagnosis is obtained.

      PMID:15350377 | DOI:10.1016/j.ygyno.2004.05.057

      View details for PubMedID 15350377
  • Loss of biological effect in prolonged fraction delivery International journal of radiation oncology, biology, physics
    Fowler JF, Welsh JS, Howard SP
    2004 May 1;59(1):242-9. doi: 10.1016/j.ijrobp.2004.01.004.
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      PURPOSE: The decrease of biologic effect if delivery of dose fractions takes more than a few minutes has been occasionally recognized in the literature but has been insufficiently studied. It has been recognized as a problem in the long exposures necessary for stereotactic radiotherapy and is also a potential problem in some applications of IMRT. Modeling repair rates is a complex function of dose per fraction, dose rate, half-times of repair, and nature of the tissue of interest (the alpha/beta ratio of intrinsic radiosensitivity to repair capacity). In this article, we model repair rates for a range of doses per fraction and draw conclusions.

      METHODS AND MATERIALS: We review the data on half-times of repair in tissues in situ in animals and human patients and conclude that a single first-order (exponential) repair rate is no longer an appropriate assumption for most tissues. At least 2 half-times of repair, and perhaps a distribution of half-times, are required. The faster components have a median half-time of 0.3 h (range, 0.08-1.2 h), and the longer components have a median of 4 h (range, 2.4->6 h). Modeling repair rates by a two-component model is the simplest approach. We have used two models of repair to represent these ranges, one with equal proportions of 0.2 h + 4.0 h half-times, the other with 0.4 h + 4.0 h half-times of repair. Data are also reviewed on the few experiments that have been reported with cell culture that investigate this problem.

      RESULTS: Computations indicate that any fraction delivery that lasts more than half an hour might experience a clinically significant loss of cell-sterilizing effect. We suggest that a loss of more than 10% in biologically effective dose should be compensated for and show modeled doses and fraction durations for which this situation seems to be likely. It will be dose, tissue, and system dependent and will require more investigation at the clinical level.

      CONCLUSION: It is suggested that any radiotherapy schedule that requires more than half an hour for the delivery of 1 fraction should have careful records made and reported, to look for a possible decrease of biologic effect with fraction duration.

      PMID:15093921 | DOI:10.1016/j.ijrobp.2004.01.004

      View details for PubMedID 15093921
  • Perillyl alcohol mediated radiosensitization via augmentation of the Fas pathway in prostate cancer cells The Prostate
    Rajesh D, Howard SP
    2003 Sep 15;57(1):14-23. doi: 10.1002/pros.10269.
    • More

      BACKGROUND: The management of hormone-insensitive locally advanced prostate cancer is difficult and complex and there is an urgent need for the development of effective chemotherapeutic agents intended for combination with currently available treatment modalities.

      METHODS: The present paper demonstrates the effectiveness of the monoterpene perillyl alcohol (POH) as potent radiosensitizer on DU145 and PC3 cell lines by performing clonogenic survival assays, cycle analysis, and assays to detect viability, apoptosis, and Fas receptor/ligand by flow cytometry.

      RESULTS: POH pretreatment resulted in a dose dependent sensitization to kill cell by radiation. Furthermore, POH treatment induced a transient G(2)/M arrest, enhanced the expression of the membrane bound form of the Fas ligand and sensitized the cells to Fas mediated apoptosis.

      CONCLUSIONS: The unique manner of radiosensitization in addition to its low toxicity profile makes POH a promising new agent for preclinical evaluation as a potential radiosensitizer in the treatment of prostate cancer.

      PMID:12886519 | DOI:10.1002/pros.10269

      View details for PubMedID 12886519
  • Perillyl alcohol as a radio-/chemosensitizer in malignant glioma The Journal of biological chemistry
    Rajesh D, Stenzel RA, Howard SP
    2003 Sep 19;278(38):35968-78. doi: 10.1074/jbc.M303280200. Epub 2003 Jun 12.
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      The prognosis for patients with malignant glioma has not significantly changed in two decades, despite advances in surgery, radiation, and chemotherapy, emphasizing the growing need for novel approaches to glioma therapy. Perillyl alcohol (POH) is a naturally occurring monoterpene that has been shown to possess chemotherapeutic as well as chemopreventive activity in animal tumor models and is currently in Phase I and Phase II clinical trials. In the present study, we have demonstrated that POH is an effective radiosensitizer at clinically relevant doses of radiation using established glioma cell lines. POH caused a transient arrest in the G2/M phase of the cell cycle and induced apoptosis in glioma cells. POH treatment sensitized glioma cells to Fas-mediated apoptosis, which was further augmented in the presence of ionizing radiation and abrogated in the presence of antagonistic antibody. POH-induced radiosensitization was partially inhibited in glioma cells expressing dominant negative Fas-associated death domain and completely inhibited in glioma cells overexpressing the cytokine response modifier A. In addition, POH treatment resulted in a dose-dependent sensitization to cisplatin and doxorubicin induced cytotoxicity in glioma cells, highlighting its usefulness as a potent radio/chemosensitizer in the treatment of malignant glioma.

      PMID:12805388 | DOI:10.1074/jbc.M303280200

      View details for PubMedID 12805388
  • Modulation of target-cell culture conditions alters susceptibility to lymphocyte-mediated lysis Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy
    Albertini MR, Howard SP, Fisch P, Lindstrom MJ, Hank JA, Gould MN, Sondel PM
    1993 May 4;13(4):243-51. doi: 10.1097/00002371-199305000-00003.
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      The culture conditions of the immortalized human breast cell line, 184B5, can be manipulated to evaluate conditions that influence target lysis by activated immune effector cells. Exponentially growing 184B5 cells (EXP) are more susceptible than growth-factor-deprived (removal of epidermal growth factor and bovine pituitary extract) 184B5 cells (GFD) to lysis by lymphokine-activated killer (LAK) cells, activated natural killer (NK) clones, and activated gamma/delta receptor expressing T-cell clones. LAK-cell lysis of contact-inhibited 184B5 cells is similar to lysis of GFD, while 184B5 cells with severe nutrient deprivation are more easily lysed than GFD by LAK cells. In a cold target inhibition assay with LAK effector populations, EXP are better inhibitors than GFD against several targets. Further analysis of the mechanism by which changes of in vitro culture conditions alter target-cell susceptibility to immune-mediated lysis may assist therapeutic strategies that involve combinations of standard therapies with biologic approaches.

      PMID:8334108 | DOI:10.1097/00002371-199305000-00003

      View details for PubMedID 8334108
  • Proliferation-independent growth factor modulation of the radiation sensitivity of human prostate cells Radiation research
    Howard SP, Groch KM, Lindstrom MJ, Messing EM, Gould MN
    1995 Aug;143(2):229-33.
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      The survival of human prostatic epithelial cells irradiated in different physiological states is reported. Exponentially growing cells and contact-inhibited cells grown and irradiated in the presence of the growth factors epidermal growth factor (EGF) and bovine pituitary extract (bPE) had overlapping radiation dose-cell survival curves. However, when EGF and bPE were removed from exponentially growing cells before irradiation, an increase in radiosensitivity was observed if the cells were replated into medium containing growth factors (EGF and bPE) immediately after irradiation. Treating cells with the nonspecific growth factor receptor antagonist suramin had similar effects as did growth factor deprivation. In contrast, when growth factor-deprived cells were maintained in this same medium for 12 h postirradiation, an increase in radiation survival was observed. This increase in survival is attributed to the repair of potentially lethal damage (PLD). Both the increase in radiosensitivity induced by deprivation of growth factor before irradiation and the repair of PLD caused by deprivation of growth factor after irradiation were independent of changes in cellular proliferation.


      View details for PubMedID 7631017
  • Rare clonal karyotypic variants in primary cultures of human breast carcinoma cells Cancer research
    Zhang R, Wiley J, Howard SP, Meisner LF, Gould MN
    1989 Jan 15;49(2):444-9.
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      Cytogenetic analyses were performed on 40 previously untreated primary human breast carcinomas, four untreated breast metastases, nine human breast fibroadenomas, and ten normal human mammary tissues, all in primary culture. The results revealed predominantly normal diploid cells with abnormal clones in two of 40 primary carcinomas and one of four metastases. 3p deletion [del(3)(p14-21)], similar to that associated with small cell lung cancer, was found in a primary tumor from a patient with bilateral breast cancer. In addition, a clone with t(1;4) was found in another primary breast carcinoma, while a t(1;5) clone was found in a metastatic tumor.


      View details for PubMedID 2910462
  • Radiosensitivity and PLDR in primary cultures of human normal and malignant mammary and prostate cells International journal of radiation biology
    Gould MN, Howard SP
    1989 Nov;56(5):561-5. doi: 10.1080/09553008914551741.
  • Influence of estradiol and tamoxifen on susceptibility of human breast cancer cell lines to lysis by lymphokine-activated killer cells Journal of immunotherapy : official journal of the Society for Biological Therapy
    Albertini MR, Gibson DF, Robinson SP, Howard SP, Tans KJ, Lindstrom MJ, Robinson RR, Tormey DC, Jordan VC, Sondel PM
    1991). 1992 Jan;11(1):30-9. doi: 10.1097/00002371-199201000-00004.
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      The design of combination hormonal and immunotherapeutic protocols for breast cancer patients may be facilitated by analysis of preclinical in vitro model systems. Estrogen receptor positive (ER+: MCF-7) and negative (ER-: MDA-MB-231) human breast cancer cell lines were utilized to evaluate the effects of tamoxifen (TAM) and estradiol (E2) on modulation of breast cancer target susceptibility to lysis by lymphokine-activated killer (LAK) cells. E2-stimulated ER+ cells were more susceptible to lysis by LAK cells than corresponding TAM-treated or control cells, while treatment of ER- cells with either E2 or TAM alone did not alter from control their susceptibility to this immune-mediated lysis. All ER+ and ER- cells tested remained sensitive after treatment with TAM to lysis by LAK cells. In addition, an adenocarcinoma reactive human-mouse chimeric monoclonal antibody (ING-1) was able to significantly boost in vivo generated LAK cell-mediated lysis of control, E2-treated, and TAM-treated ER+ and ER- cells. These in vitro results provide a preclinical rationale for in vivo testing of TAM, interleukin-2 (IL-2), and breast cancer reactive antibody-dependent cellular cytotoxicity facilitating antibody in patients with refractory or high risk breast cancer.

      PMID:1734946 | DOI:10.1097/00002371-199201000-00004

      View details for PubMedID 1734946

Contact Information

Steven Howard, MD, PhD

600 Highland Avenue,
Box 3684 Clinical Science Center
Madison, WI 53792